Causal Relationship Between Blood Proteome and Retinitis Pigmentosa: A Mendelian Randomization Study

Purpose: Identification and validation of potential therapeutic targets for retinitis pigmentosa (RP). Methods: We utilized genome-wide significant protein quantitative trait locus (pQTL) data for 4719 plasma proteins derived from 35,559 individuals, alongside RP summary statistics from 126,454 individuals of European ancestry. The analysis employed several methods, including inverse variance weighted, weighted median, MR-Egger, and weighted mode, complemented by sensitivity analyses. Key proteins were validated through summary data-based Mendelian randomization (SMR) analysis and heterogeneity in dependent instruments (HEIDI) testing. Additionally, we constructed protein-protein interaction (PPI) networks, as well as Gene Ontology (GO) and functional enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Finally, the functions of the core proteins were validated through in vitro cellular experiments. Results: Mendelian randomization (MR) analysis identified 10 plasma proteins associated with RP. Acid phosphatase 6 (ACP6), adaptor-related protein complex 1 subunit gamma 2 (AP1G2), and annexin A2 (ANXA2) were confirmed as key candidate proteins through SMR and HEIDI testing. ACP6 and AP1G2 were linked to the mitigated phenotypic severity of RP, serving as protective factors, whereas ANXA2 was associated with an exacerbated of phenotypic severity of RP, indicating its potential role as a modulator of disease progression. Enrichment analysis revealed that these proteins participate in biological processes such as lipid metabolism, vesicle-mediated transport, and inflammatory responses. These experiments confirmed that overexpression of ACP6 or AP1G2 or knockdown of ANXA2 significantly inhibited H2O2-induced apoptosis and reactive oxygen species (ROS) accumulation in ARPE-19 cells. Conclusions: By integrating proteomic and genomic data and in vitro functional experiments, this study identified ACP6, AP1G2, and ANXA2 as potential therapeutic targets for RP. These findings provide a foundation for future drug development and offer new insights into the molecular mechanisms underlying RP. Translational Relevance: Identified causal proteins ACP6/AP1G2 and ANXA2 offer direct therapeutic targets for developing novel treatments to alleviate RP progression.